Methods for enhancing the effectiveness of drugs,which employ an alkylated phenoxy (polyethanol)



United States Patent METHODS FOR ENHANCING THE EFFECTIVE- NESS OF DRUGS,WHICH EMPLOY AN ALKYL- ATED PHENOXY (POLYETHANOL) Herbert S. Polin,Veyrier pres Geneve, Geneva, Switzerland N0 Drawing. Filed Feb. 12,1964, Ser. N0. 344,223 lint. Cl. A61k 27/00, 9/00 US. Cl. 424182 ClaimsABSTRACT OF THE DISCLOSURE Methods and compositions are disclosed forparenteral administration, which include the administration of a drug,such as a stimulant, blocking agent or vasoconstrictor, in conjunctionwith a surface active agent, such as an alkylated phenoxy (polyethanol),for enhancing the effectiveness of the drug.

The invention described in this application relates to the use ofcertain chemical compoundsfor potentiating drugs. More particularly, itis concerned with the use of various surface-active agents for thispurpose whereby an enhancement of the physiological effect of the drugis thus achieved.

The surface-active agents which come within the purview of the presentinvention are all non-toxic in nature and, in general, are selected fromsuch standard groupings as quaternary ammonium compounds,sulfosuccinates, polyoxyethylene' higher alkanols, sulfuric acidmonoesters of said alkanols, alkylated phenoxyethanols and alkylatedphenoxy (polyethanols), and the like, with the last named grouping beingthe most preferred. The preferred surface-active agents of thisinvention all possess the following general structural formula:

RQm 0132011.)..011

wherein R is an alkyl radical of from one to eighteen carbon atoms and nis an interger of from one to thirty, inclusive. Typical membercompounds of this group include those which have the above formulawherein R is nonyl or octyl and n=6 or 9-l0', respectively.

The drugs which are applicable to this invention are only limited in thesense that they must otherwise be bound at their receptor sites by alipid barrier layer (i.e., in the absence of the surface-active agent),and preferably, they are also drugs which areparenterally-administrable. Typical examples of the wide variety ofdifferent type drugs concerned here include stimulants such asadrenaline, nor-adrenaline and digitoxin, blocking agents such aslidocaine as well as various forms of curare, and vasoconstrictors likeserotonin and so forth.

In general, the amount of surface-active agent to be employed withrespect to the drug of choice for the purposes at hand may vary over awide range, but it is usually desirable in practice to use at leastabout 0.1% by weight of said agent with respect to the drug in order toachieve effective results, i.e., a substantial degree of potentiation.Optimum results, however, have been obtained with from about 0.1% toabout 10% by weight of the agent with respect to the weight of the drug.For instance, the physiological effects of a drug such as adrenalinehave been potentiated by as much as 100% over the normal control valueby the use of or practice of this invention. Hence, in view of thisremarkable degree of drug-activity enhancement thus achieved, it ispossible to use lesser amounts of a given drug for a particular statedpurpose and still achieve the same effect quantitatively as regardsorder of magnitude of response that "ice would normally be achieved whenthe drug is used alone, i.e., in the absence of surfactant. For example,normal drug doses in the case of the representative compounds previouslymentioned have been reduced by as much as to gain the same responsenormally achieved when the drug is used alone at the aforementionedhigher level.

In carrying out the process of this invention, the surfactantpotentiator can be administered either before or after the parenteraladministration of the drug itself provided that the interval between thetwo is not too great, i.e., not generally in excess of about fifteenminutes. However, it is preferred in practice to administer the twocomponents together simultaneously, i.e., in combination via anadmixture comprising said components as will be hereinafter discussed inmore detail. In either case, the surfactant potentiator is said to beadministered in conjunction with the drug.

For purposes of parenteral administration, solutions of the drug to beadministered in sesame or peanut oil or in aqueous-propylene glycol orN,N-dimethylformamide may be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts if available orpreparable. Such aqueous solutions should be suitably buffered ifnecessary, wherein the liquid diluent is first rendered isotonic withsufficient saline or glucose. All these solutions are particularlyvaluable for intravenous, intramuscular and intraperitioneal injectionpurposes. In this connection, the sterile aqueous media employed arereadily obtained by standard techniques well-known to those in the art.For instance, when distilled water is ordinarily used as the liquiddiluent, the final preparation can be passed through a suitablebacterial filter, such as a sintered glass filter or a diatomaceousearth or unglazed poreclain filter. Preferred filters of this typeinclude the Berkefeld, the Chamberland and the asbestos disc-metal Seitzfilter, wherein the fluid is sucked through the filter candle into asterile container with the aid of a suction pump. Needless to say,aseptic conditions must necessarily be maintained throughout all theseoperations which are directely connected with the preparation of theaforesaid injectable solutions.

This invention is further illustrated by the following examples, whichare not to be construed in any way or manner as imposing limitationsupon the scope thereof. On the contrary, it is to be clearly understoodthat resort may be had to various other embodiments, modifications andequivalents thereof which readily suggest themselves to those skilled inthe art without departing from the spirit of the present inventionand/or the scope of the appended claims.

EXAMPLE I A dial-aenesthetized dog was rigged for registration ofheart-rate and respiration in the standard way and canulated for readyinjection of various parenteral solutions. When the animal registered asteady state, adrenaline in a 0.1% solution (in oil) was administeredvia this route at the 0.2-0.6 ml. dose level, i.e., a thresholdconcentration, and readings were thereafter taken with respect to theamplitude and persistance of response of said animal, as well as to itsrecovery with time. After final recovery, a dose of the same drug wasprepared having only one-tenth the concentration of the aforesaid testdose. This was then mixed with 2 ml. of 0.01% Trition X-l00 in Ringer(saline) solution, and the resulting mixture was injected into the sameanimal as before via the canula [Trition X400 is the registeredtrademark name of the Rohn & Haas Co. of Philadelphia, Pa. for asurface-active agent of the formula The results obtained in this mannerare such that the dose-response effect which is produced in the case ofthe Triton-containing solution at least equals that which is caused bythe more concentrated adrenaline solution lacking the surfactant agent.The tests also established that the animal shows no real response to theTriton X-lOO when employed at this concentration alone in Ringersolution.

Example II The procedure described in Example I was repeated with anisolated organ rather than an intact animal as the substrate of choice.In this particular case, a frog heart was used which, in turn, requiredthat it be mounted for Ringer perfusion with a T in the line so as tofacilitate side-tube introduction of the drug as well as large-scale(volume) washing of the system. Otherwise, the experimental routine ortest procedure is essentially the same as in Example I for the intactanimal. In like manner, the dose-response results obtained withadrenaline in the present case are also substantially the same, i.e.,the effect produced by the Triton surfactant on the drug is ofsubstantially the same order of magnitude as that reported in Example Ifor the intact animal experiment.

Example III Adrenaline was injected into the isolated heart as inaccordance with the procedure of Example II, but lacking the addedTriton X-lOO at this point. After normal response and full recovery,followed by a multiple-washing, a small quantity (2 ml.) of Triton X100in Ringer solution at the 0.01% concentration level was injected intothe so-treated organ without any drug. It was observed that the heartimmediately responded with the same reaction that the adrenaline gave inthe first instance, thereby indicating that a large unused portion ofthe drug had still been present in the isolated, washed organ (no doubt,bound in the lipid barrier) prior to the admin istration of thesurfactant.

In like manner, substantially the same results were also achieved withthe intact dog when the above procedure was repeated using thisparticular animal instead of the aforesaid isolated organ.

Example IV The procedure described in Example I is repeated in dogsusing other compounds in place of adrenaline. Thus, for instance, thefollowing compounds have been used on an individual basis:nor-adrenaline, tube or bamboo curare, pot curare and gourd or calabash,lidocaine, serotonin and digitoxin. In each case, the results obtainedare substantially the same as those reported previously for adrenalinein Example 1.

Example V The procedure of Example I is followed except that othersurface-active agents are employed in place of Triton X100 and these arelisted below as follows:

In each and every case, the results obtained are substantially the sameas those reported previously in Example I.

' Example VI Example VII The procedure described in Example II wasrepeated using other isolated organs in place of that of the frogsheart. Among the organs specifically tested in this manner are thehearts of dogs and eels, as Well as muscle and nerve preparations takenfrom all three species of animals. In each and every case, the resultsobtained are substantially identical with those for the frog heart.

What is claimed is:

1. A method for pofentiating the physiological effect of a drug which isbound by a lipid barrier layer at the receptor site, said methodcomprising the step of parenterally administering to an animal, a drugselected from the group consisting of adrenaline, nor-adrenaline,curare, lidocaine, serotonin and digitoxin in conjunction with anon-toxic surface-active agent of the formula RQWCHQCHQDOH wherein R isan alkyl radical of from one to eighteen carbon atoms and n is aninteger of from one to thirty, inclusive, said surface-active agentbeing present in an amount of from about 0.1% to about 10% by weightbased on the drug.

2. A method as claimed in claim 1 wherein the surface-active agent isadministered simultaneously with the drug by admixture therewith.

3. -A method as claimed in claim 1 wherein the surfaceactive agent isadministered separately and up to 15 minutes subsequent to theadministration of the drug.

4. A method as claimed in claim 1 wherein R is nonyl and 11:6.

5. A method as claimed in claim 1 wherein R is 6. A method as claimed inclaim 5 wherein the drug employed is adrenaline.

7. A method as claimed in claim 5 wherein the drug employed islidocaine.

8. A method as claimed in claim 5 wherein the drug employed isserotonin.

9. A method as claimed in claim 5 wherein the drug employed isdigitoxin.

10. A method as claimed in claim 1 wherein R is nonyl, n equals 6 andand the drug is adrenaline.

References Cited UNITED STATES PATENTS 2,767,116 10/1956 Cheney 167-82.92,803,583 8/1957 Petersen 16758.l 2,976,213 3/1961 Murphey l6758.13,228,834 l/l966 Gans 167-58.1

OTHER REFERENCES C. A., vol. 60, p. 16371 f (1964).

ALBERT T. MEYERS, Primary Examiner.

S. I. FRIEDMAN, Assistant Examiner.

US. Cl. X.R.

